Metformin Attenuates Myocardial Ischemia–Reperfusion Injury in Rats by Modulating JNK Pathway and Inhibiting PANoptosis Mechanisms

IF 3.4 4区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Therapeutics Pub Date : 2025-10-07 DOI:10.1155/cdr/4642838

Biao Hou, Xuejian Hou, Liyue Zhang, Tingting Liu, Yang Li, Ran Dong

{"title":"Metformin Attenuates Myocardial Ischemia–Reperfusion Injury in Rats by Modulating JNK Pathway and Inhibiting PANoptosis Mechanisms","authors":"Biao Hou, Xuejian Hou, Liyue Zhang, Tingting Liu, Yang Li, Ran Dong","doi":"10.1155/cdr/4642838","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Purpose</h3>\n \n <p>Myocardial ischemia–reperfusion injury (MIRI) is a condition in which the heart is aggravated when blood flow is restored after tissue damage caused by ischemia. Metformin (Met), a widely prescribed antidiabetic medication, has demonstrated promising cardioprotective properties, particularly through its anti-inflammatory, antiapoptotic, and metabolic regulatory mechanisms. This study investigates the cardioprotective effects of Met in a rat model of MIRI, focusing on its modulation of the c-Jun N-terminal kinase (JNK) pathway and inhibition of PANoptosis mechanisms.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>The proportion of myocardial infarction was determined by triphenyl tetrazole chloride (TTC) staining. Wheat germ agglutinin (WGA) staining is used to determine whether myocardial cells are hypertrophic and other pathological conditions. Serum markers of myocardial injury along with inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence and Western blotting were employed to evaluate myocardial cell PANoptosis and the involvement of the JNK pathway.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>After MIRI, TTC staining revealed apparent myocardial infarction, and WGA staining showed significant myocardial cell hypertrophy. There was also a marked increase in myocardial injury markers, inflammatory factors, and reactive oxygen species (ROS). Met significantly reduced the myocardial injury area and notably lowered serum levels of c-TnI, CK-MB, LDH, IL-6, TNF-<i>α</i>, and ROS. Immunofluorescence and Western blot analyses demonstrated that Met attenuates myocardial cell PANoptosis by inhibiting JNK phosphorylation and reducing ROS generation. The cardioprotective effect of Met was reversed by the addition of anisomycin (ANI). The protective effect of JNK-specific inhibitors administered as monotherapy was found to be comparable to that of Met. The aforementioned results suggest that the regulation of the JNK pathway is a critical factor contributing to its protective effect.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>The cardioprotective effect of Met in the rat model of MIRI is mediated through the regulation of the JNK pathway and PANoptosis. These findings suggest that Met may provide a potential therapeutic approach for treating MIRI.</p>\n </section>\n </div>","PeriodicalId":9582,"journal":{"name":"Cardiovascular Therapeutics","volume":"2025 1","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/cdr/4642838","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/cdr/4642838","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose

Myocardial ischemia–reperfusion injury (MIRI) is a condition in which the heart is aggravated when blood flow is restored after tissue damage caused by ischemia. Metformin (Met), a widely prescribed antidiabetic medication, has demonstrated promising cardioprotective properties, particularly through its anti-inflammatory, antiapoptotic, and metabolic regulatory mechanisms. This study investigates the cardioprotective effects of Met in a rat model of MIRI, focusing on its modulation of the c-Jun N-terminal kinase (JNK) pathway and inhibition of PANoptosis mechanisms.

Methods

The proportion of myocardial infarction was determined by triphenyl tetrazole chloride (TTC) staining. Wheat germ agglutinin (WGA) staining is used to determine whether myocardial cells are hypertrophic and other pathological conditions. Serum markers of myocardial injury along with inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence and Western blotting were employed to evaluate myocardial cell PANoptosis and the involvement of the JNK pathway.

Results

After MIRI, TTC staining revealed apparent myocardial infarction, and WGA staining showed significant myocardial cell hypertrophy. There was also a marked increase in myocardial injury markers, inflammatory factors, and reactive oxygen species (ROS). Met significantly reduced the myocardial injury area and notably lowered serum levels of c-TnI, CK-MB, LDH, IL-6, TNF-α, and ROS. Immunofluorescence and Western blot analyses demonstrated that Met attenuates myocardial cell PANoptosis by inhibiting JNK phosphorylation and reducing ROS generation. The cardioprotective effect of Met was reversed by the addition of anisomycin (ANI). The protective effect of JNK-specific inhibitors administered as monotherapy was found to be comparable to that of Met. The aforementioned results suggest that the regulation of the JNK pathway is a critical factor contributing to its protective effect.

Conclusion

The cardioprotective effect of Met in the rat model of MIRI is mediated through the regulation of the JNK pathway and PANoptosis. These findings suggest that Met may provide a potential therapeutic approach for treating MIRI.

Abstract Image

查看原文本刊更多论文

二甲双胍通过调节JNK通路和抑制PANoptosis机制减轻大鼠心肌缺血再灌注损伤

心肌缺血再灌注损伤（心肌缺血再灌注损伤，心肌缺血再灌注损伤）是指心肌缺血组织损伤后，血流恢复后心脏功能加重的一种疾病。二甲双胍（Metformin, Met）是一种广泛使用的抗糖尿病药物，已被证明具有良好的心脏保护作用，特别是通过其抗炎、抗细胞凋亡和代谢调节机制。本研究探讨了Met在MIRI大鼠模型中的心脏保护作用，重点研究了其对c-Jun n -末端激酶（JNK）通路的调节和对PANoptosis的抑制机制。方法采用氯化三苯四唑（TTC）染色法测定心肌梗死比例。小麦胚芽凝集素（WGA）染色用于确定心肌细胞是否肥厚及其他病理状况。采用酶联免疫吸附法（ELISA）检测心肌损伤血清标志物及炎症因子水平。采用免疫荧光和Western blotting检测心肌细胞PANoptosis及JNK通路的参与情况。结果MIRI后，TTC染色显示明显心肌梗死，WGA染色显示心肌细胞明显肥大。心肌损伤标志物、炎症因子和活性氧（ROS）也明显增加。蛋氨酸显著减少心肌损伤面积，显著降低血清c-TnI、CK-MB、LDH、IL-6、TNF-α、ROS水平。免疫荧光和Western blot分析表明，Met通过抑制JNK磷酸化和减少ROS生成来减轻心肌细胞PANoptosis。加入大霉素（ANI）后，Met的心脏保护作用被逆转。jnk特异性抑制剂作为单药治疗的保护作用被发现与Met相当。上述结果提示，JNK通路的调控是其发挥保护作用的关键因素。结论Met在MIRI大鼠模型中的心脏保护作用是通过调控JNK通路和PANoptosis介导的。这些发现表明Met可能为治疗MIRI提供一种潜在的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cardiovascular Therapeutics 医学-心血管系统

CiteScore

5.60

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Cardiovascular Therapeutics (formerly Cardiovascular Drug Reviews) is a peer-reviewed, Open Access journal that publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of new cardiovascular therapies. Articles on translational research, pharmacogenomics and personalized medicine, device, gene and cell therapies, and pharmacoepidemiology are also encouraged. Subject areas include (but are by no means limited to): Acute coronary syndrome Arrhythmias Atherosclerosis Basic cardiac electrophysiology Cardiac catheterization Cardiac remodeling Coagulation and thrombosis Diabetic cardiovascular disease Heart failure (systolic HF, HFrEF, diastolic HF, HFpEF) Hyperlipidemia Hypertension Ischemic heart disease Vascular biology Ventricular assist devices Molecular cardio-biology Myocardial regeneration Lipoprotein metabolism Radial artery access Percutaneous coronary intervention Transcatheter aortic and mitral valve replacement.